Background

HER2 Mutations in NSCLC

• Human epidermal growth factor receptor 2 (HER2) mutations are oncogenic drivers in NSCLC and are found in approximately 3% of patients with NSCLC1-3

− HER2 is considered a distinct molecular target as HER2 mutations tend to be mutually exclusive from aberrations in other driver mutations4

− Median overall survival (OS) is shorter and the incidence of brain metastasis is greater in patients with HER2m advanced NSCLC compared with patients with tumors harboring other driver mutations1,2,5

• There are no approved HER2-targeted therapies for patients with NSCLC6

− Several studies with HER2-targeted tyrosine kinase inhibitors in this population have been conducted or are ongoing; however, clinical responses with these HER2-targeted agents in HER2m NSCLC produced limited activity and inconsistent results, with objective response rates (ORRs) ranging from 0 to 30%7-11

− Trastuzumab emtansine, a HER2 antibody–drug conjugate (ADC), has shown more encouraging activity, with an ORR of 44%; receptor–ADC internalization is thought to be a mechanism of action12-13

• For patients with HER2m NSCLC, chemotherapy and/or immune checkpoint inhibitors remain the standard of care but have limited activity in second or later line settings

− With combination therapy, ORR ranges from 12 to 23% and median duration of response (DOR) is ≈5 months14,15

− Moreover, immune checkpoint inhibitor monotherapy may not be effective in patients with HER2m NSCLC (ORR, 7%)16

T-DXd Is Designed to Deliver an Optimal Antitumor Effect

• T-DXd is an ADC with 3 components (Figure 1)17,18:

− Humanized anti-HER2 immunoglobulin G1 monoclonal antibody that has the same amino acid sequence as trastuzumab

− Topoisomerase I inhibitor payload, an exatecan derivative

− Tetrapeptide-based cleavable linker

Figure 1. Structure of T-DXd17-19

Humanized anti-HER2 IgG1 mAb17-19

Deruxtecan17,18

Tetrapeptide-based cleavable linker Topoisomerase I

inhibitor payload (DXd)

HER2, human epidermal growth factor receptor 2; IgG1, immunoglobulin G1; mAb, monoclonal antibody; T-DXd, trastuzumab deruxtecan.

• T-DXd has been approved to treat adult patients with

− HER2-positive unresectable/metastatic breast cancer who received prior chemotherapy or ≥2 prior anti-HER2–based regimens, at the 5.4 mg/kg every 3 weeks (Q3W) dose20-23

− HER2-positive advanced/metastatic gastric cancer who received a prior trastuzumab-based regimen (United States and Israel) or whose disease progressed after chemotherapy (Japan), at the 6.4mg/kg Q3W dose20,21,23

• T-DXd is approved in the United States and Japan with boxed warnings for interstitial lung disease (both countries) and embryo-fetal toxicity (United States only)20,21

• In the DS8201-A-J101 dose escalation and expansion phase 1 trial (NCT02564900), 2 recommended phase 2 doses of T-DXd were established: 5.4 mg/kg and 6.4 mg/kg Q3W24

• T-DXd 6.4 mg/kg Q3W was investigated in a phase 2 trial (DESTINY-Lung01; NCT03505710) in patients with metastatic HER2m NSCLC (Table 1),25 with the primary analysis presented at ESMO 2021 (Abstract #LBA45)26

− Although T-DXd 5.4 mg/kg and T-DXd 6.4 mg/kg have shown clinical efficacy in multiple cancer indications,27-29 T-DXd 5.4 mg/kg has not been tested in patients with HER2m NSCLC

− T-DXd 5.4 mg/kg and T-DXd 6.4 mg/kg are being evaluated in patients with HER2-overexpressing NSCLC (DESTINY-Lung01; NCT03505710)

− T-DXd in combination with durvalumab is being evaluated in patients with HER2-expressing NSCLC (DESTINY-Lung03; NCT04686305)

• T-DXd is also being evaluated in studies of other solid tumor types, including a HER2m tumor-agnostic trial (DESTINY-PanTumor01; NCT04639219)

Key Inclusion Criteria

• Adults (according to local regulation) and able to provide informed consent

• Metastatic NSCLC with a known activating HER2 mutation (by local detection)

• One or more lines of previous treatment, including platinum therapy

• Presence of ≥1 measurable lesion confirmed by BICR, based on RECIST v1.1

• ECOG PS of 0 or 1• LVEF ≥50% within 28 days before randomization• Willing and able to provide an adequate tumor

tissue sample

Key Exclusion Criteria

• Known driver mutation in the EGFR or BRAF gene or a known ALK or ROS1 fusion

• History of ILD/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening

• MI ≤6 months before randomization or symptomatic CHF

• Spinal cord compression or clinically active CNS metastases

• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder

Study Endpoints

Primary • Confirmed ORR by BICR-assessed RECIST v1.1a

Secondary

Efficacy

• ORR by investigator-assessed RECIST v1.1

• DOR

• DCR

• PFS

• OS

Safety

• AEs, including TEAEs, SAEs, and AEs of special interest graded according to NCI-CTCAE v5.0

• ECOG PS, vital sign measurements, ophthalmologic findings, standard clinical laboratory parameters, ECG parameters, ECHO/MUGA findings, and radiologic findings

Pharmacokinetics

• Serum concentrations of T-DXd, total anti-HER2 antibody, and MAAA 1181

Immunogenicity

• Incidence of antidrug antibodies

Health Economics and Outcomes Research

• PROs of change from baseline in EORTC core QLQ-C30 and EORTC QLQ-LC13 scale scores and time to deterioration in EORTC QLQ-C30 scores

AE, adverse event; BICR, blinded independent central review; DCR, disease control rate; DOR, duration of response; ECG, electrocardiogram; ECHO, echocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; EORTC, European Organization for Research and Treatment of Cancer; HER2, human epidermal growth factor receptor 2; MUGA, multi-gated acquisition; NCI-CTCAE v5.0, National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRO, patient-reported outcome; QLQ-C30, quality-of-life questionnaire core 30; QLQ-LC13, quality-of-life questionnaire for lung cancer trials; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1; SAE, serious adverse event; T-DXd, trastuzumab deruxtecan; TEAE, treatment-emergent adverse event. aConfirmed ORR defined as the proportion of patients with a best overall response of confirmed complete response or partial response as assessed by blinded data review and based on RECIST v1.1.

Methods

Study Design and Population

• DESTINY-Lung02 is a global, multicenter, 2-arm, randomized phase 2 study (Figure 2)

Figure 2. Study Design

Patients with HER2m NSCLC

Stratified by patients who:• Received prior anti-PD-1 and/or anti-PD-L1 treatment• Received neither

Planned

N = 150

T-DXd5.4 mg/kg Q3W

n = 100

T-DXd6.4 mg/kg Q3W

n = 50

R2:1

HER2m, human epidermal growth factor receptor 2–mutated; NSCLC, non–small cell lung cancer; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; Q3W, every 3 weeks; R, randomization; T-DXd, trastuzumab deruxtecan.

This presentation is the intellectual property of the authors. Please contact Dr. Egbert F. Smit at e.smit@nki.nl for permission to reprint and/or distribute any part of this poster. Poster presented at the European Society of Medical Oncology (ESMO) Congress 2021; September 16-21, 2021.

AcknowledgmentsWe thank the patients who are participating in this study, as well as their families and caregivers. This study is sponsored by Daiichi Sankyo, in collaboration with AstraZeneca. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for T-DXd (DS-8201). Medical writing support was provided by Toinette Labuschagné, MSc, and Cindy M. Rigby, PhD, of ApotheCom and funded by Daiichi Sankyo.

References1. Pillai RN et al. Cancer. 2017;123:4099-4105. 2. Arcila ME et al. Clin Cancer Res. 2012;18:4910-4918.3. Mazieres J et al. J Clin Oncol. 2013;31:1997-2003.4. Zhao J et al. JCO Precis Oncol. 2020;4:411-425. 5. Offin M et al. Cancer. 2019;125:4380-4387.6. National Comprehensive Cancer Network. NCCN clinical practice

guidelines in oncology (NCCN guidelines): non–small cell lung cancer (Version 5.2021). June 15, 2021. Accessed June 17, 2021. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.

7. Hyman DM et al. Nature. 2018;554:189-194.8. Lai WV et al. Eur J Cancer. 2019;109:28-35.

9. Dziadziuszko R et al. J Thorac Oncol. 2019;14:1086-1094.10. Kris MG et al. Ann Oncol. 2015;26:1421-1427. 11. Zhou et al. J Clin Oncol. 2020;38:2753-2761.12. Li BT et al. J Clin Oncol. 2018;36:2532-2537. 13. Li BT et al. Cancer Discov. 2020;10:674-687.14. Garon EB et al. Lancet. 2014;384:665-673. 15. Borghaei H et al. N Engl J Med. 2015;373:1627-1639.16. Mazieres J et al. Ann Oncol. 2019;30:1321-1328.17. Nakada T et al. Chem Pharm Bull (Tokyo). 2019;67(3):173-185. 18. Ogitani Y et al. Clin Cancer Res. 2016;22(20):5097-5108. 19. Trail PA et al. Pharmacol Ther. 2018;181:126-142.

20. Enhertu [prescribing information]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; 2021.

21. Enhertu [prescribing information]. Tokyo, Japan: Daiichi Sankyo Co., Ltd; 2020.

22. Enhertu [summary of product characteristics]. Munich, Germany: Daiichi Sankyo Europe GmbH; 2021.

23. Enhertu. The Israeli Drug Registry [database online]. Ministry of Health Israel. Accessed August 18, 2021. https://data.health.gov.il/drugs/index.html#!/medDetails/167%2074%2036545%2000.

24. Doi T et al. Lancet Oncol. 2017;18(11):1512-1522.

25. Smit E et al. Presented at: 2020 World Conference on Lung Cancer Singapore; January 28-31, 2021; Virtual. Abstract MA11.03.

26. Li BT et al. Presented at: 2021 European Society of Medical Oncology (ESMO) Congress; September 16-21, 2021; Virtual. Abstract LBA45.

27. Tamura K et al. Lancet Oncol. 2019;20:816-826.28. Shitara K et al Lancet Oncol. 2019;20:827-836.29. Tsurutani J et al Cancer Discov. 2020;10:688-701.

Disclosures Dr. Egbert F. Smit reports paid consulting or advisory roles (fees to the institution) from AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MSD, Novartis, Pfizer, Regeneron, Roche/Genentech, Roche Diagnostics, and Takeda; and research funding (to the institution) from AstraZeneca, Bristol Myers Squibb, Roche/Genentech, Merck, and MSD outside the submitted work.

Trastuzumab Deruxtecan (T-DXd) in Patients With HER2-Mutated (HER2m) Metastatic Non–Small Cell Lung Cancer (NSCLC): A Phase 2 Study (DESTINY-Lung02)Egbert F. Smit,1 Bob T. Li,2 Julien Mazieres,3 David Planchard,4 Kazuhiko Nakagawa,5 Koichi Goto,6 Luis Paz-Ares,7 Silvia Novello,8 James Chih-Hsin Yang,9 Myung-Ju Ahn,10 Geoffrey Liu,11 Kenneth O’Byrne,12 Mehreteab Aregay,13 Ryota Shiga,13 Kapil Saxena,13 Kaline Pereira,13 Gerold Meinhardt,13 Pasi A. Jänne14

1Netherlands Cancer Institute, Amsterdam, Netherlands; 2Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Institut Universitaire du Cancer, Toulouse, France; 4Department of Medical Oncology, Gustave Roussy, Villejuif, France; 5Kindai University Hospital, Osaka, Japan; 6National Cancer Center Hospital East, Kashiwa, Japan; 7Hospital Universitario 12 de Octubre, Madrid, Spain; 8University of Turin, AOU San-Luigi-Orbassano (TO), Orbassano, Italy; 9National Taiwan University Cancer Center, Taipei, Taiwan; 10Samsung Medical Center, Seoul, South Korea; 11Princess Margaret Cancer Centre, Toronto, ON, Canada; 12Princess Alexandra Hospital, Brisbane, QLD, Australia; 13Daiichi Sankyo Inc., Basking Ridge, NJ, USA; 14Dana-Farber Cancer Institute and Belfer Center for Applied Cancer Science, Boston, MA, USA 1361TiP

ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene, serine/threonine kinase; BICR, blinded independent central review; CHF, congestive heart failure; CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; ILD, interstitial lung disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSCLC, non–small cell lung cancer; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

Statistical Analyses

• Efficacy analyses will be completed on the full analysis set, which will include all patients who are randomly assigned to a study treatment

− ORR will be estimated along with the 2-sided 95% CIs

− Median DOR, PFS, and OS will be summarized using the Kaplan–Meier method

• Safety analyses will be performed on the safety analysis set, which will include all patients who receive ≥1 dose of T-DXd

• Pharmacokinetic (PK) analyses will be performed using the PK analysis set, which will include all patients who receive ≥1 dose of T-DXd and have measurable serum concentrations of T-DXd

− Serum concentrations of T-DXd, total anti-HER2 antibody, and MAAA 1181a will be listed and summarized using descriptive statistics at each time point by dose level

• Immunogenicity will be assessed by characterizing the incidence and titer of antidrug antibodies

• Descriptive statistics will be calculated to summarize the change from baseline in symptoms, physical functioning, and general health-related quality-of-life scales at each scheduled assessment time point by dose level

Table 1. Interim Analysis Efficacy Results in Patients With HER2m NSCLC (DESTINY-Lung01)24

Response Assessment by ICR Cohort 2 Patients (N = 42)

Confirmed ORR, % n (95% CI)

61.9 26 (45.6-76.4)

DCR, % n (95% CI)

90.5 38 (77.4-97.3)

Median DOR, months (95% CI) NE (5.3-NE)

Median PFS, months (95% CI) 14 (6.4-14.0)

Median OS, months (95% CI) NE (11.8-NE)

Data cutoff: November 25, 2019. DCR, disease control rate; DOR, duration of response; HER2m, human epidermal growth factor receptor 2-mutated; ICR, independent central review; NE, not estimable; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Enrollment

• This trial is actively enrolling, with approximately 150 patients to be enrolled from 45 sites in Australia, Canada, France, Italy, Japan, Netherlands, South Korea, Spain, Taiwan, and the United States

• For more information or to refer a patient, please visit ClinicalTrials.gov (NCT04644237)

Enrolling150 patients

Objective

• This randomized phase 2 study will characterize the benefit-risk profile of T-DXd in patients with metastatic HER2m NSCLC who have experienced disease recurrence or progression during or after ≥1 regimen of prior anticancer therapy, including platinum therapy

− The efficacy and safety of the 5.4 mg/kg dose in patients with HER2m NSCLC will be evaluated for the first time, and the efficacy and safety of the 6.4 mg/kg dose will be further assessed in this population

− The primary endpoint is confirmed ORR by blinded independent central review